Tumour specific regulation of telomerase RNA gene expression visualized by in situ hybridization

Maintenance of telomere structure by the ribonucleoprotein enzyme telomerase is considered central to the development of most human cancers, However, regulatory mechanisms governing telomerase expression during oncogenesis are largely unknown. We address potential tumour-specific regulation of telomerase RNA gene expression by RNA in situ hybridization to over 300 tumour samples of germ cell and epithelial origin, Twenty-six per cent of non-small cell lung cancers (NSCLC), expressed detectable levels of the telomerase RNA gene (hTR), and interestingly expression was almost confined to squamous carcinomas (41%), being rare in pulmonary adenocarcinomas and large-cell anaplastic carcinomas (P=0.006), Low frequency hTR expression was also associated with adenocarcinoma of the breast (13%), and ovary (17%), In comparison, hTR expression was detected in 43% of cervical cancers with no significant differences in frequency between squamous-cell carcinoma and adenocarcinoma or in transitions between intraepithelial neoplasia and invasive carcinoma, In contrast to the common epithelial cancers, the malignant cells in 73% of testicular germ-cell tumours (seminomas and teratomas), expressed hTR consistent with hTR expression in normal testicular germ cells, Differentiated tissues within ovarian germ cell tumours and in testicular teratomas lacked detectable hTR expression, These studies show that different tumour types have distinct patterns of hTR expression, which has implications for our understanding of mechanisms regulating telomerase activity and for targeting the telomerase RNA component as an anti-cancer therapy

Amplification, increased dosage and in situ expression of the telomerase RNA gene in human cancer

Telomere length is maintained by the enzyme, telomerase, which has been linked to cellular immortality and tumour progression, However, the reasons for the high levels of telomerase found in human tumours are unknown, We have mapped the human telomerase RNA gene, (hTR), to chromosome 3q26.3 and show the hTR gene to be amplified in four carcinomas, (2/33 cervix, 1/31 head and neck, 1/9 lung), In addition, increased copy numbers of the hTR locus was also observed in 97% of tumours, By in situ hybridisation, the histological distribution of high levels of hTR expression could be demonstrated in a lung tumour and its metastasis with hTR amplification, These results are the first report of genetic alterations involving a known component of telomerase in human cancer, Indeed, it is also the first report of the amplification of a specific locus within the chromosome 3q region frequently subject to copy number gains in human tumours, In addition, we also show for the first time the histological distribution of the RNA component of telomerase in human tumours

Mapping of the gene for the mouse telomerase RNA component, Terc, to chromosome 3 by fluorescence in situ hybridization and mouse chromosome painting

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